Therapy of Hepatitis C Jay H. Hoofnagle, M.D. Director, Liver Disease Research Branch National Institutes of Health Bethesda, Maryland, USA

Transcription

1 Institute of Medicine Committee on a National Strategy for the Elimination of Hepatitis B and C: December 2015 Therapy of Hepatitis C Jay H. Hoofnagle, M.D. Director, Liver Disease Research Branch National Institutes of Health Bethesda, Maryland, USA

2 Disclosures Jay H. Hoofnagle I am an employee of the Federal Government and have no personal conflicts of interest to report I supervise several extramural and intramural projects that have varying degrees of industry support via Clinical Trial Agreements or CRADA with the NIH: Gilead, BMS, Roche & Merck I will discuss off-label used of new agents for hepatitis C and will mention when this is the case

3 Elimination and Prevention Three Forms Primary: prevent the infection Vaccine, Public Health, Decrease exposures Secondary: prevent the disease Screening, Management, Therapy Tertiary: prevent complications/death Nonspecific and Specific Therapies

4 Antiviral Therapy of Hepatitis C Two Eras Interferon ( ) Mono or combined therapy, Ribavirin, Direct Acting Agents Direct Acting Agents (2012-present) Initially with interferon, Later DAAs alone Future? Direct host acting agents Perhaps more applicable to HBV and HDV

5 Therapy of Hepatitis C The Interferon Era Began with demonstration that interferon alfa had beneficial effects (1986) and could induce long-term remissions (1988). With identification of HCV (1989), interferon was shown to reduce HCV RNA levels and lead to long term loss of virus in a proportion of cases. Approved for use in hepatitis C in U.S. in 1991 Rapidly became clear that interferon alfa by itself had very limited efficacy and applicability A second or even third drug was needed

6 Progress in Therapy of Hepatitis C: % 80% Sustained Response 60% 40% 20% % 25% % E-o-T Relapse 0% 6-10% 15-20% 15-20% IFN IFN IFN high dose SVR 6 mo 12 mo mo

7 Ribavirin Guanosine analogue with potent activity against several flaviviruses in cell culture

8 Ribavirin Markedly Increases the Response Rate to Interferon in Chronic Hepatitis C 80% SVR Rate 70% 60% 50% 40% 30% 20% 10% 0% 13% IFN 12 mo NEJM 1998 Lancet % IFN & Rbv 6 mo McHutchison 38% IFN & Rbv 12 mo 19% IFN 12 mo 35% IFN & Rbv 6 mo Poynard n = 912 n = % IFN & Rbv 12 mo

9 Peginterferon Further Increases the Response Rate in Chronic Hepatitis C SVR 80% 70% 60% 50% 40% 30% 20% 10% 0% NEJM 2002 Lancet % IFN & Rbv 48 wks Fried 56% Peg & Rbv 48 wks 13% 47% Manns n = 1121 n = 1530 alfa-2a IFN & Rbv 48 wks alfa-2b 54% Peg & Rbv 48 wks

10 Progress in Therapy of Hepatitis C: % Sustained Response 80% 60% 40% 20% % % 34% % % 0% IFN IFN IFN/R IFN/R PegIFN/R 6 mo 12 mo 6 mo 12 mo 12 mo

11 CHRONIC HEPATITIS C Virologic Responses HCV RNA (Log IU/mL) Antiviral Therapy Non-Response Relapse Undetectable SVR Weeks After Start of Therapy

12 SVR as an Endpoint for Therapy A sustained virologic response (SVR) appeared to presage a long-term clearance of HCV Late relapses uncommon (1-2% after 10 years) The liver disease does not progress Hepatocellular carcinoma occurs, but largely among those with cirrhosis at the time of treatment Appears to be a cure of the chronic viral infection Initially SVR defined by 24 week follow up, later 12 weeks found adequate for clinical trials

13 Lack of Progress in Therapy of Hepatitis C : End of the Interferon Era 100% Sustained Response 80% 60% 40% 20% % % 34% % % % 0% IFN IFN IFN/R IFN/R PegIFN/R PegIFN/R 6 mo 12 mo 6 mo 12 mo 12 mo 6-18 mo

14 HCV Genome Organization ~9.6 kb Single-stranded, positive-sense RNA genome Protease/Helicase Polymerase 5 3 C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Structural Proteins Nonstructural Proteins (Enzymes)

15 Three HCV Protease Inhibitors Efficacy in Chronic Hepatitis C, genotype 1 100% Boceprevir NEJM 2011 Telaprevir NEJM 2011 Simeprevir Lancet % 68% 75% 80% SVR 60% 40% 20% 40% Peg & Rbv 48 wks Boc Peg & Rbv 44% Peg & Rbv 48 wks Tel Peg & Rbv 50% Peg & Rbv 48 wks Sim Peg & Rbv 0% Poordad Jacobson Manns & Jacobson n = 938 n = 1088 n = 785

16 Problems with Interferon Based Therapy Response rates of 70-80% are achieved with protease inhibitors added to peginterferon & ribavirin But the tolerability of interferon remains a limiting factor And addition of protease inhibitors worsens tolerability Up to half of patients do not qualify for treatment Only half can tolerate the side effects or will accept therapy In a community practice situation, sustained responses are achieved in only 10-15% of infected patients The solution is an all-oral, interferon-free regimen

17 The Era of Direct Acting Antiviral Agents for Hepatitis C Interferon-free regimens 2012 to the Present

18 HCV Non-Structural Regions HCV Protease Inhibitors Protease/Helicase 5 3 NS2 NS3 NS4A NS4B NS5A NS5B RNA polymerase Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Asunaprevir Faldaprevir Proteomimetic drugs Genotype specific: 1a and 1b Resistance rapidly develops Can have difficult side effects Drug-drug interactions common -previrs FDA approved: 2015

19 Telaprevir Complex macromolecule that mimics the amino acid sequence cleaved by genotype 1 protease

20 HCV Non-Structural Regions NS5A Replication Complex Inhibitors Protease/Helicase 5 3 NS2 NS3 NS4A NS4B NS5A NS5B RNA polymerase Block formation of the HCV replication complex Varying genotypic restriction Well tolerated Potent activity -asvir Daclatasvir Ledipasvir Ombitasvir Elbasvir Velpatasvir FDA approved: 2015

21 Daclatasvir Dimeric molecule that blocks HCV NS5A

22 HCV Non-Structural Regions HCV RNA Polymerase Inhibitors Protease/Helicase RNA polymerase 5 3 NS2 NS3 NS4A NS4B NS5A NS5B Nucleoside Pan-genotypic Well Tolerated Non-Nucleoside* More restricted activity Side effects -buvir Sofosbuvir Dasabuvir* Deleobuvir* [Ribavirin?] FDA approved: 2015

23 Sofosbuvir 2 deoxy-2 fluoro-2 methyl uridine monophosphate with an alaninate cap

24 Therapy of Hepatitis C All Oral Regimens: DAAs Daclatasvir & Asunaprevir (2012) Daclatasvir & Sofosbuvir (2013) Simeprevir & Sofosbuvir (2013) Ledipasvir & Sofosbuvir (Harvoni: 2014) Dasabuvir, Ombitasvir & Paritaprevir/r with or without ribavirin (Viekira Pak: 2014) Velpatasvir & Sofosbuvir (2015) Grazoprevir & Elbasvir (2016) (Year of first publication of results)

25 Response Rate Ledipasvir & Sofosbuvir for Genotype 1 HCV 100% 99% 94% 90% 12 weeks 12 weeks 80% [n=214] [n=109] Afdahl et al 2014: NEJM 70% Naïve Experienced

26 Response Rate Ledipasvir & Sofosbuvir for 8 vs 12 wks Genotype 1,Treatment Naïve Patients 100% 94% 95% 90% Kowdley et al 2014: NEJM 80% 8 weeks 12 weeks 70% [n=215] [n=216] Sofosbuvir & Ledipasvir

27 Response Rate Ledipasvir & Sofosbuvir for 8 vs 12 wks Genotype 1,Treatment Naïve Patients 100% 98.8% 98.3% 98.5% 90% 90.2% 8 wks 12 wks 8 wks 12 wks Post-hoc, per protocol analysis: Kowdley et al 2014: NEJM 80% [92] [85] [123] [131] HCV > 6 Million IU HCV < 6 Million IU

28 Response Rate Dasabuvir, Ombitasir, Paritaprevir/ritonavir and Ribavirin for Genotype 1 HCV 100% 96% 96% 90% 80% 12 weeks Feld et al 2014: NEJM 12 weeks Zeuzem et al 2014: NEJM 70% [n=473] Naïve [n=297] Experienced

29 Non-Response Rates 12 Weeks of Therapy: Naïve Patients 4.6% 3.8% n=7 n=10 1.5% n=2 n=1 n=3 n=7 n=1 n=214 n=216 n=473

30 Response Rate Sofosbuvir & Velpatasvir for Chronic Hepatitis C 12 weeks. Naïve & Experienced. Cirrhotic & non-cirrhotic. 100% 98% 99% 99% 95% 100% 97% 100% 90% 80% Feld et al Foster et al NEJM: % [210] [118] [238] [277] [116] [35] [100] 1a 1b Genotype

31 Sofosbuvir and Velpatasvir Non-SVR Rates [n=0] [n=13] [n=6] 4.7% n=2 Feld et al Foster et al NEJM: 2015 [n=901] 3% 1.9% n=2 n=1 1% n=1 0.4% n=1 n=11 0% n=1 0% 1% [n=210] [n=118] [n=234] [n=277] [n=116] [n=35] [n=41]

32 A Challenging Cohort: Decompensated Cirrhosis Patients with cirrhosis and decompensation (Childs-Pugh Class B & C) are particularly challenging to treat. A beneficial response may be very valuable Restoring health and disability Avoiding death or liver transplantation Response rates are less optimal Adverse events are more frequent and more likely to be serious and even life-threatening Interferon-based therapies were associated with considerable morbidity and mortality

33 Response Rate Chronic Hepatitis C and Cirrhosis Phase III Trials of DAAs 100% Childs Pugh Class A 96% 98% Childs Pugh Class B & C 94% 92% 92% 90% 12 weeks 24 weeks 12 weeks 24 weeks 12 weeks 86% 80% 24 weeks [n=208] [n=172] [n=118] [n=133] [n=90] [n=90] 70% D-O-Pr/Rbv S-L S-V Poordad 2014 Reddy 2015 Curry 2014

34 What are the side effects of the all-oral direct acting antiviral agents? Most publications have stated that the all oral DAA regimes are generally well tolerated The controlled trials of new DAA regimens have generally compared different treatment regimens Few studies have included placebo control Ribavirin has a well defined spectrum of adverse events (anemia, lymphopenia, itching, rash). Only one study of DAA therapy without ribavirin has included untreated, placebo controls

35 Adverse Event Rate Sofosbuvir & Velpatasvir vs Placebo for Chronic Hepatitis C for 12 weeks: Adverse Events 30% 28% 29% 25% S-V Placebo 20% 15% 10% 5% 0% Headache 20% 20% 12% 11% 9% 8% [210] [118] Fatigue Nausea Insomnia Diarrhea 8% 8% 8% 7% 7% 6% 2% 0% Asthenia Arthralgias SAEs 19 SAEs occurred in 15 of 624 Sof-Vel but none of the 116 placebo recipients (p = 0.15) Feld et al NEJM: 2015

36 Serious Adverse Event Rate Serious Adverse Event Rates Clinical Trials of DAAs for Chronic Hepatitis C 5% 4% D-O-Pr & Rbv S-L S-V 3% 2% 2.1% 2.0% 2.3% 2.4% 1.9% 1% 1.0% 1.2% 0% 0% Feld 2014 Zeuzem 2014 Ferenci % Afdhal 2014 Kowdley % Feld 2015 Foster 2015 D-O-P/r & Rbv Placebo S-L S-V Eight Phase III trials published in the New England Journal Medicine: 12 week regimens only

37 Adverse Event Rate 100% 90% 80% 70% Chronic Hepatitis C and Cirrhosis Adverse Events Childs Pugh Class A 91% 76% Childs Pugh Class B & C 94% 60% 50% 40% Any Adverse Event Any Adverse Event Any Adverse Event 30% 20% 10% 0% [n=380] 1 death 6% SAE [n=251] No reported 6% SAE [n=180] 6 deaths D-O-Pr/Rbv S-L S-V Poordad 2014 Reddy 2015 Curry % SAE

38 Will the excellent response rates in clinical trials be reproduced in clinical practice? SVR rates to interferon-based regimens are often not reproducible in clinical practice: the real world. HCV-TARGET: an investigator initiated registry of patients treated in community & academic practice. Initial evaluation of S-L in 942 patients with hepatitis C. 97% 97% 95% n=154 n=627 n=161 Terrault et al: AASLD 2015

39 Limiting Factors: Barriers Host Factors Interferon Based Age Gender Race IL28b Obesity Fibrosis Cirrhosis Comorbidities (many) Direct Acting Agents Cirrhosis (decompensated) End-stage renal disease? Viral Factors Extraneous Factors Genotype HCV RNA level Genetic diversity Viral kinetics Previous therapy Costs Genotype Costs

40 Successful Therapy of Hepatitis C Newer regimens of oral direct acting antivirals have response rates of 95-99% Twelve weeks of treatment Minimal side effects Little need for intense monitoring Highly effective, short-term, well tolerated therapy that can be administered easily Promises to make a real impact on the morbidity and mortality of this disease

41 Progress in Therapy of Hepatitis C 100% 2015 >95% Sustained Response Rate 80% 60% 40% 20% % % % % % 0% IFN IFN IFN/R PegIFN/R P/R/PI DAAs 6 mo 12 mo 6-12 mo 6-12 mo 6-12 mo 3 mo

42 Total Cost of Therapy Costs of Therapy of Hepatitis C $100,000 $80,000 $60,000 $40,000 $20,000 $0 Genotype K 86K K K K 2.5K IFN IFN IFN/R PegIFN/R P/R/PI DAAs 6 mo 12 mo 12 mo 12 mo 12 mo 3 mo

43 The Costs of Success The remaining major barrier is its cost Harvoni (L-S) for 12 weeks: $96,000 Viekira Pak (D-O-Pr) for 12 weeks: $83,000 Burden to the health care system in the next few years: in excess of $100,000,000,000 In the United States only ~25% of persons with hepatitis C have private insurance; the rest are in public health care programs or uninsured Enormous burden to an already overburdened medical care system

44 The Costs of Success The costs of HCV agents are unreasonable Prices charged are unjustified Estimated costs of production: $ / course Costs of development: millions not billions Highly effective and life-extending Therapy will not decrease medical care costs in the United States, and may increase them Part of an accelerating excessive pricing of lifesustaining and life-extending medications

45 Elimination and Prevention Three Forms Primary: prevent the infection Vaccine, Public Health, Decrease exposures Secondary: prevent the disease Screening, Management, Therapy Tertiary: prevent complications/death Nonspecific and Specific Therapies